Postmenopausal Osteoporosis
Conditions
Keywords
Amgen, Phase 1, Postmenopausal, Osteoporosis
Brief summary
This is a multi-center, open-label, drug-drug interaction study in postmenopausal women with osteoporosis.
Detailed description
Approximately 27 subjects (Group A: 18; Group B: 9) will receive a 2 mg oral dose of midazolam on day 1 followed by a 24 hour PK collection. Subjects randomized to Group A will receive a single 60 mg subcutaneous (SC) dose of denosumab on day 2 administered in the abdomen. On study day 16, another 2 mg oral dose of midazolam will be administered to all subjects (Groups A and B) followed by a 24 hour PK collection. The primary analysis to determine the effect of denosumab on the PK of midazolam will be based on data from subjects in Group A only.
Interventions
DRUGDenosumab
Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.
DRUGMidazolam
All subjects will receive two oral dose administrations of midazolam.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Between 45 to 75 years of age * Postmenopausal women * Osteoporosis
Exclusion criteria
* Use of any known inhibitors of cytochrome P450 3A4/P-gp (CYP3A4) within 14 days or 5 half lives, whichever is longer; or grapefruit juice or grapefruit containing products within 7 days prior to investigational product administration * Use of any known CYP3A4 inducers within 30 days or 5 half-lives, whichever is longer, prior to investigational product administration * Use of any herbal medicine with a known impact on CYP3A4 (eg, St. John's wort) within 30 days prior to investigational product administration * Current use of medications prescribed for osteoporosis treatment * Use of midazolam within 14 days prior to investigational product administration * Influenza or other vaccination within 28 days of screening * Previous exposure to denosumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. |
| Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability |
| Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability |
| Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Serum C-Telopeptide Concentration | Baseline (day 2 pre-dose) to day 16 | This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. |
| Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. |
| Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. |
| Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration | Baseline (day 2 pre-dose) to day 16 | This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. |
| Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability. |
| Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability. |
| Summary of Serum Denosumab Concentration | Baseline (day 2 pre-dose) to day 16 | This table summarizes serum Denosumab for Midazolam with Denosumab group. The Lower Limit Of Quantification (LLOQ) is 20 ng/mL. On Day 2 (pre-dose), the true value is below LLOQ, and is treated as 0 in the analysis. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Midazolam With Denosumab 2 mg oral dose of Midazolam on Day 1 and Day 16, 60 mg subcutaneous dose of Denosumab on Day 2. Out of 21 subjects enrolled and randomized, 19 subjects received investigation product. | 19 |
| Midazolam Only 2 mg oral dose of Midazolam on Day 1 and Day 16. Out of 9 subjects enrolled and randomized, 8 subjects received investigation product. | 8 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Midazolam With Denosumab | Midazolam Only | Total |
|---|---|---|---|
| Age, Continuous | 64.42 years STANDARD_DEVIATION 6.16 | 66.25 years STANDARD_DEVIATION 5.34 | 64.96 years STANDARD_DEVIATION 5.89 |
| Age, Customized <65 years | 7 Participants | 3 Participants | 10 Participants |
| Age, Customized >=65 years and <75 years | 12 Participants | 4 Participants | 16 Participants |
| Age, Customized >=75 years | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 6 Participants | 23 Participants |
| Sex: Female, Male Female | 19 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 19 | 6 / 18 | 10 / 18 | 2 / 8 | 1 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 | 0 / 18 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group | Cmax Subject: Inter-subject | 0.15 ng/mL | Standard Deviation 0.064 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group | Cmax Residual: Intra-subject | 0.07 ng/mL | Standard Deviation 0.023 |
Primary
Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC (0-t) Residual: Intra-subject | 0.07 ng*hr/mL | Standard Deviation 0.025 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC (0-inf) Subject: Inter-subject | 0.21 ng*hr/mL | Standard Deviation 0.085 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC (0-t) Subject: Inter-subject | 0.19 ng*hr/mL | Standard Deviation 0.079 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC (0-inf) Residual: Intra-subject | 0.08 ng*hr/mL | Standard Deviation 0.027 |
Primary
Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Midazolam With Denosumab | Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | AUC (0-t) | 1.10 unitless |
| Midazolam With Denosumab | Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | AUC (0-inf) | 1.12 unitless |
Primary
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Midazolam With Denosumab | Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | 1.11 unitless |
Secondary
Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group | Cmax Subject: Inter-subject | 0.23 ng/mL | Standard Deviation 0.143 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group | Cmax Residual: Intra-subject | 0.06 ng/mL | Standard Deviation 0.035 |
Secondary
Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | AUC (0-inf) Subject: Inter-subject | 0.31 ng*hr/mL | Standard Deviation 0.175 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | AUC (0-inf) Residual: Intra-subject | 0.03 ng*hr/mL | Standard Deviation 0.015 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | AUC (0-t) Subject: Inter-subject | 0.27 ng*hr/mL | Standard Deviation 0.155 |
| Midazolam With Denosumab | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | AUC (0-t) Residual: Intra-subject | 0.03 ng*hr/mL | Standard Deviation 0.016 |
Secondary
Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Midazolam With Denosumab | Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | AUC (0-t) | 0.98 unitless |
| Midazolam With Denosumab | Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | AUC (0-inf) | 0.98 unitless |
Secondary
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Population: The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Midazolam With Denosumab | Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | 1.05 unitless |
Secondary
Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
Time frame: Baseline (day 2 pre-dose) to day 16
Population: Serum CTX will be collected for Midazolam with Denosumab group only. The PD analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum CTX concentrations are determinable on when assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam With Denosumab | Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration | -87.52 percentage |
Secondary
Summary of Serum C-Telopeptide Concentration
This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
Time frame: Baseline (day 2 pre-dose) to day 16
Population: Serum CTX will be collected for Midazolam with Denosumab group only. The PD analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum CTX concentrations are determinable on when assessed.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Summary of Serum C-Telopeptide Concentration | Baseline (day 2 pre-dose) | 0.4655 ng/mL | Inter-Quartile Range 0.0698 |
| Midazolam With Denosumab | Summary of Serum C-Telopeptide Concentration | Day 16 | 0.0606 ng/mL | Inter-Quartile Range 0.003 |
| Midazolam With Denosumab | Summary of Serum C-Telopeptide Concentration | Change from baseline to Day 16 | -0.4079 ng/mL | Inter-Quartile Range 0.0702 |
Secondary
Summary of Serum Denosumab Concentration
This table summarizes serum Denosumab for Midazolam with Denosumab group. The Lower Limit Of Quantification (LLOQ) is 20 ng/mL. On Day 2 (pre-dose), the true value is below LLOQ, and is treated as 0 in the analysis.
Time frame: Baseline (day 2 pre-dose) to day 16
Population: Serum Denosumab will be collected for subjects in Midazolam with Denosumab group only. The analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum Denosumab concentrations are determinable when assessed.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Midazolam With Denosumab | Summary of Serum Denosumab Concentration | Day 2 (Pre-dose) | 0 ng/mL | — |
| Midazolam With Denosumab | Summary of Serum Denosumab Concentration | Day 16 (0hr) | 5820 ng/mL | Standard Deviation 1800 |
| Midazolam With Denosumab | Summary of Serum Denosumab Concentration | Day 17 (24hr) | 5500 ng/mL | Standard Deviation 1940 |